Proteins that are structurally related to tumor necrosis factor (TNF) are collectively referred to as the TNF superfamily. TL1A, a TNF superfamily member, is a TNF-like cytokine that binds to the death-domain receptor (DR)3 and provides costimulatory signals to activated lymphocytes. Through this interaction, TL1A induces secretion of IFN-gamma and may, therefore, participate in the development of T helper-1-type effector responses.
TL1A is a type II transmembrane protein and has been designated TNF superfamily member 15 (TNFSF15). TL1A is expressed predominantly by endothelial cells and monocytes, and its expression is inducible by TNF-a and IL-1a. Migone et al., Immunity, 16:479-92 (2002). TL1a is upregulated by the proinflammatory cytokines TNF and IL-1 and also by immune complexes (IC). Hsu et al., Exp. Cell Res., 292:241-51 (2004).
TL1A mediates signaling via its cognate receptor DR3, a death receptor whose activation was known to induce both death and survival factors. TL1A, like TNF, is also presumed to circulate as a homotrimeric soluble form. Kim et al., J. Immunol. Methods, 298(1-2):1-8 (March 2005).
TL1A binds with high affinity to death receptor 3 (DR3) which is a member of the death-domain containing TNF receptor family, and is also termed Wsl-1, Apo-3, TRAMP, and LARD, and now designated TNF receptor superfamily member 25 (TNFRSF25). Depending on the cell context, ligation of DR3 by TL1A can trigger one of two signaling pathways, activation of the transcription factor NF-kB or activation of caspases and apoptosis. TL1 functions in T cell costimulation and Th1 polarization. On activated T cells, TL1A functions specifically via its surface-bound receptor DR3 to promote cell survival and secretion of proinflammatory cytokines. The secreted decoy receptor 3 (DcR3), a soluble protein of the tumor necrosis factor receptor (TNFR) superfamily, blocks the action of TL1A. Kim et al., “Identification of naturally secreted soluble form of TL1A, a TNF-like cytokine,” J Immunol Methods, 298:1-8 (2005).
Potential Therapeutic Targets
Allergy and Asthma
Th2 polarization of CD4 T cells with elevated IgE levels and production of IL-13 by NKT cells are major cause of lung inflammation in Allergy and asthma. TL1A plays a major role in allergic lung inflammation (Fang et al J. Exp. Med. 2008). TL1A co-stimulates IL-4 and IL-13 production in NKT cells. Blocking TL1A and DR3 interaction by TL1A antibody or dominant negative TL1A mutant abolishes lung inflammation.
Lung and Colon Carcinomas
Members in the TNF and its receptor superfamilies regulate immune responses and induce apoptosis. DR3 is preferentially expressed by T lymphocytes and upregulated during T cell activation. The ligand for DR3 is TL1A. TL1A also binds decoy receptor DcR3/TR6, which is expressed in several lung and colon carcinomas and in some normal tissues. TL1A is upregulated by proinflammatory cytokines TNF and IL-1. TL1A is a longer variant of TL1 (also called VEGI).
Atherosclerosis
In addition, TL1A has also been reported to be angiostatic and to induce metalloproteinase and IL-8 gene expression (Su et al., Exp. Cell Res., 312:266-277 (2006); Kang et al., Cytokine, 29:229-235 (2005)). Indeed, TL1A and DR3 may be involved in the pathogenesis of atherosclerosis by increasing the production of proinflammatory cytokines and chemokines and decreasing plaque stability by inducing extracellular matrix-degrading enzymes (Kang et al., Cytokine, 29:229-235 (2005)).
Rheumatoid Arthritis
There is also evidence to suggest that TL1A/DR3 is involved in the etiology of rheumatoid arthritis (Bossen et al., J. Biol. Chem., 281(20):13964-13971 (May 19, 2006).
Inflammatory Bowel Disease
Researchers have found an association of the expression of TL1A and inflammatory bowel disease (Prehn et al., Clin. Immunol., 112:66-77 (2004); Bamias et al., J. Immunol., 171:4868-4874 (2003)).
Th1-Mediated Intestinal Diseases, Such as Crohn's Disease
Crohn's disease is a severe inflammatory bowel disorder that strikes young adults (ages 20-30). The condition is thought to originate from predisposing genetic and environmental factors that cause an imbalance of effector (proinflammatory) and regulatory T cell responses, resulting in inflammation of the gastrointestinal mucosa and disease.
The TL1A/DR3 pathway plays an important role in Th1-mediated intestinal diseases, such as Crohn's disease. Konstantinos et al., The Journal of Immunology, 2005, 174: 4985-4990 (2005); Bamias et al., J. Immunol., 171:4868-74 (2003). Blockade of the TL1A/DR3 pathway may, therefore, offer therapeutic opportunities in Crohn's disease.
TL1A augments IFN-gamma production by anti-CD3 plus anti-CD28 and IL-12/IL-18-stimulated peripheral blood (PB) T cells. Activation of DR3 by TL1A induced the formation of a signaling complex containing TRADD, TRAF2, and RIP and activated the NF-kB and the ERK, JNK, and p38 mitogen-activated protein kinase pathways. Kang et al., Cytokine, 29:229-35 (2005). TL1A can be released to circulate as a homotrimeric soluble form. Wen et al., “TL1A-induced NF-kappaB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells,” J. Biol. Chem., 278:39251-8 (2003).
Death receptors and their ligands play a key role in the maintenance of tissue homeostasis and the physiological regulation of programmed cell death. Binding of a death ligand induces oligomerization of the receptor, recruitment of an adapter protein via a conserved cytoplasmic signaling element termed the death domain, activation of caspases, and induction of apoptosis. Young et al., Proc Natl. Acad. Sci. USA., 103(22): 8303-8304 (May 30, 2006).
Although death receptors such as Fas/Apo-1/CD95, TNF-R1, TRAIL-R1, TRAIL-R2, or DR3 were initially characterized as inducers of apoptosis, there is growing evidence that these receptors also have nonapoptotic functions, including regulation of the adaptive immune response. Bamias et al., Proc. Natl. Acad. Sci. USA, 103:8441-8446 (2006), report that TL1A is expressed by lamina propia dendritic cells and that it functions by increasing the proliferation of memory cells, but not naïve CD4+ T cells, and synergizes with IL-12 and/or low-dose stimulation of the T cell receptor to strongly enhance IFN-γ gene expression. IFN-γ expression in the gut has been considered a marker of inflammation, and many strategies for treating Crohn's disease rely on broad attempts to suppress the immune-activated state. However, such approaches (steroid treatment and immunosuppressive drugs) do not focus on the gut specifically and thus have their own complications. Targeted therapies based on the use of antagonists of TNF-α were introduced with success in the 1990s, and the results reported in ref. 1 suggest that therapy directed specifically against TL1A or its receptor may provide an alternative targeted therapy for this debilitating disorder.
As reported in Bamias et al., Proc. Natl. Acad. Sci. USA., 103:8441-8446 (2006), TL1A seems to have a most profound effect when expressed in the gut during inflammation. TL1A synergizes in the induction of IFN-γ expression in human T cells when combined with IL-12/18, although increased expression can also be observed in natural killer cells (Migone et al., Immunity., 16:479-492 (2002); Papadakis et al., J. Immunol., 174:4985-4990 (2005); Papadakis et al., J. Immunol., 172:7002-7007 (2004)). Bamias et al., Proc. Natl. Acad. Sci. USA., 103:8441-8446 (2006), is the first report of a similar observation in mouse models of Crohn's disease and extends earlier data by showing that the synergy occurs when the T cell receptor is weakly stimulated or T cells are treated with IL-12. Although in Bamias et al. no synergy is observed when TL1A treatment is combined with IL-18, this result may not be surprising because both IL-18 and TL1A signal through NF-κB. Whereas the initial report by Migone et al. on TL1A demonstrated that it was a T cell costimulatory signal, Bamias et al. demonstrate that it is the memory T cell that most strongly responds, consistent with the increased capacity of this T cell population to express IFN-γ. Because this population does proliferate, it also expresses higher levels of the TL1A receptor, thus further enhancing the ability of the cells to proliferate and express IFN-γ. This finding might be considered somewhat surprising given that the only known receptor of TL1A is DR3, a death domain-containing receptor, and it might have been hypothesized that triggering this receptor would lead to cell death. (TL1A signals through DR3, its only known cell surface receptor. TL1A also binds to the soluble decoy receptor (DcR3)). However NF-κB-dependent antiapoptotic genes, such as inhibitor of apoptosis 2, have been shown to be induced by TL1A (Wen et al., J. Biol. Chem., 278:39251-39258 (2003)), and therefore triggering of apoptosis vs. proliferation may be cell-type dependent.
Current treatment options for Crohn's disease include the monoclonal antibody against TNF-α, infliximab (Remicade; Centocor, Inc., Horsham, Pa.), the monoclonal antibody Adalimumab (brand name Humira; Abbott), as well as antiinflammatories (e.g., sulfasalazine), cortisone or steroids (e.g., prednisone), immune system suppressors (e.g., 6-mercaptopurine), and antibiotics. However, infliximab is the only treatment option having a high degree of specificity; the remaining treatment options have a low specificity. Proc Natl Acad Sci U.S.A., 103(22): 8303-8304 (May 30, 2006). This means that the treatment is not targeted to the disease area. While infliximab has a high specificity and is generally well tolerated, infliximab can cause recrudescence of tuberculosis infection and worsening of heart failure, demyelinating disease, and an increased incidence of lymphoma.
Therefore, there remains a need in the art for compositions that can be used in the treatment and diagnosis of diverse inflammatory and immune diseases and disorders, such as allergy/asthma, rheumatoid arthritis, multiple sclerosis, Crohn's disease, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, type 1 diabetes and transplant rejection. The present invention, directed to monoclonal antibodies against TL1A, satisfies this need.